Antagonists of CD117 (cKit) signaling inhibit mast cell accumulation in healing skin wounds.
Mast cells (MCs) have important functional roles in leukocyte recruitment, pain, and wound healing, and increased tissue resident MC function has been associated with several fibrotic diseases. Consequently, the study of MCs in situ can be a direct approach to studying the pharmacodynamic impact of MC-directed therapeutics in tissues. Here we describe an automated laser scanning cytometry assay that was used to characterize the kinetics of MC accumulation in healing skin wounds and to study the effect of inhibiting CD117 (cKit) signaling. The number of tryptase-positive MCs approximately doubled 14 days after cutaneous injury in nonhuman primates. Treatment of animals with anti-CD117 or imatinib mesylate (Gleevec) reduced MC accumulation at the edge of healing wounds in mice and nonhuman primates, respectively. In translating this MC assay to become a biomarker for human studies, no differences in dermal MC numbers were evident between genders, ages or body mass index from 20 healthy donors. These data suggest that skin is a practical and useful tissue for tracking pharmacodynamic effects of MC-directed therapies.
Zoog
Stephen J
SJ
Department of Clinical Immunology, Amgen Inc., Thousand Oaks, California 93021, USA.
Itano
Andrea
A
Trueblood
Esther
E
Pacheco
Efrain
E
Zhou
Lei
L
Zhang
Xuxia
X
Ferbas
John
J
Ng
Gordon Y
GY
Juan
Gloria
G
D000818:Animals; D001549:Benzamides; D002522:Chlorocebus aethiops; D006801:Humans; D000068877:Imatinib Mesylate; D047569:Laser Scanning Cytometry; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D010879:Piperazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000276:immunology*; D053802:Tryptases / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D053802:Tryptases